Computational Investigations into Two-Photon Fibril Imaging Using the DANIR-2c Probe

Abstract

The design of novel fibril imaging molecules for medical diagnosis requires the simultaneous optimization of fibril-specific optical properties and binding specificity toward amyloid fibrils. Because of the possibility to monitor internal organs and deep tissues, the two-photon probes that can absorb in the infrared (IR) and near-IR (NIR) region with a significant two-photon absorption cross section are of immense interest. To contribute to this exploration of chemical compounds suitable for two-photon fibril imaging, we have computationally studied the one- and two-photon properties of a donor–acceptor-substituted DANIR-2c probe, which was used for in vivo detection of β-amyloid deposits using fluorescence spectroscopy. In particular, a multiscale computational approach was employed involving molecular docking, molecular dynamics, hybrid QM/MM molecular dynamics, and coupled-cluster/MM to study the binding of the studied probe to amyloid fibril and its one- and two-photon absorption properties in the fibrillar environment. Multiple binding sites are available for this probe in amyloid fibril, and the one corresponding to the largest binding affinity exhibits also the largest and experimentally meaningful two-photon absorption cross section, thus demonstrating the potential of the studied probe in two-photon microscopy.

Promising Molecular Architectures for Two-Photon Probes in the Diagnosis of α-Synuclein Aggregates

“…They are known to undergo photon-induced isomerization upon absorption of multiple photons [ 16 ]. Similarly, malononitrile derivatives have emerged as effective two-photon probes for monitoring fibrils [ 17 , 18 ], while thiophene derivatives have been used as luminescence probes of α-synuclein assemblies [ 19 ]. Finally, tetrapyrrolic macrocycles like phthalocyanines and porphyrins have shown anti-fibrillogenic properties against α-synuclein-based aggregates [ 20 , 21 , 22 ].…”